Editor’s note: Prof Patrick Cramer is Director at the Max Planck Institute for Biophysical Chemistry in Göttingen and the Laureate of the 2020 Otto Warburg Medal. His research group is examining how the switches in the nucleus of the cell work, which ensure that selected genes are active at a specific time and in specific cells. To enable this, Prof Cramer has visualized central steps of transcription in molecular detail and shown their relevance for gene regulation in eukaryotic cells.
Due to the Covid-19 pandemic, the award ceremony was postponed and presented at a virtual GBM awards event today.
Elsevier’s Petra Ullrich interviewed Prof Cramer about the importance of his research, his international work experiences and guiding criteria to conducting outstanding research.
Congratulations on receiving the Otto Warburg Medal! In view of the numerous awards that you’ve been recognized with over the years, what does this award mean to you?
Receiving the Otto Warburg Medal is very special to me. The German Society for Biochemistry and Molecular Biology feels a little like home to me because there are so many fine colleagues who are interested in related topics.
Also, when I look at the list of previous Warburg Medal winners, I see many outstanding colleagues who I admire and are role models for me. Just to give you an example, Max Perutz obtained the Medal in 1993. The next year, I worked as an undergraduate research student at Cambridge and met Max Perutz there. I remember him pointing out a rigorous way to analyze my crystallographic data, and also that I was able to participate in a symposium on the occasion of his 80th birthday that took place at the Royal Society in London. What an experience!
Finally, receiving the Warburg medal also makes me feel very thankful. There were so many excellent coworkers involved in our work, and over the decades, my family was very important and always supportive.
You and your team have laid important foundations for understanding the basic principles of the transcription process and its regulation. Could you explain why this research is important to all of us and society overall?
Indeed, transcription and its central enzymes, the RNA polymerases, are of crucial biomedical importance. Let me give you some examples. In cancer cells, transcription is dysregulated, and many cancer-driving oncogenes are direct regulators of transcription. Also, RNA polymerases are important drug targets. The tuberculosis drug rifampicin is an inhibitor of the bacterial RNA polymerase. Viral RNA polymerases are also targeted by widely used drugs, whether it is HIV, the Herpes virus or the novel coronavirus. RNA polymerases are also of great biotechnological importance. For example, the fabulous mRNA vaccines that are currently used worldwide to fight the coronavirus pandemic are produced with a very efficient RNA polymerase from phage origin. In all these cases, understanding RNA polymerase enzymes and the process of transcription is essential.
You once called the RNA polymerase the “machine of life.” Could you explain what exactly you mean by this?
Life as we know it is based on a DNA genome that contains all information to build and sustain an organism. However, DNA just stores information – that means the genome is silent. It must be given voice in a process called gene expression. The first step in gene expression is transcription, and transcription is catalyzed by RNA polymerases. And it is the products of transcription that give rise to cellular function. These RNA products often code for proteins, which are responsible for highly diverse tasks in the cell. Proteins bring about metabolism, energy production, cell communication and much more. The central role of transcription as a first step in gene expression is also the reason why embryo development is mainly regulated at the level of RNA polymerase function. Transcription regulation also underlies the first steps in the immune response and our circadian clock.
At the age of only 30, you went to Stanford University and worked there with Roger Kornberg, who would go on to win the Nobel Prize. Could you share some of your experiences from your time at a US university with us? How did this influence the way you conduct research today?
It was a very intense time, and I did not get much sleep during these years. I could combine my prior know-how of X-ray crystallography that I gained during my PhD work at EMBL in Grenoble with the biochemical know-how on RNA polymerase II in the Kornberg lab at Stanford.
During the first year, I found that polymerase crystals could be dehydrated and shrunk when incubated in certain buffer solutions, and this enabled me to dramatically improve their inner order and thus the resolution of the diffraction data that could be obtained from these crystals. I then collected novel inorganic compounds from other labs around the world and spent many nights at the synchrotron searching for crystals that were successfully modified with heavy metal compounds for solving the phase problem. When I was able to first see the 8 zinc ions in the polymerase with the use of a so-called anomalous difference Fourier map, I was so excited that I jumped up from my chair at the beam line of the Stanford synchrotron and went outside to see the sunrise over Silicon Valley. That moment, it was clear I would solve the 3-dimensional structure of RNA polymerase II, the enzyme that copies our genes. There was no doubt about the importance of such insights for biology and medicine.
An important skill I learned from Roger Kornberg was to write clearly and make the reader understand and enjoy the presented science. Roger was very good at encouraging me to do the best possible science. Of course it was great news when — a few years later in 2006 — he received the Nobel Prize in Chemistry for the structural basis of transcription. These early years at Stanford were also intense for us as a family – our second child was born in 2000.
What are your goals for the near future?
We would like to understand how transcription works on the natural template in cells: chromatin. We also wish to pioneer new experimental approaches. For example, we would like to transcribe a genome in the test tube for the first time. Importantly, we hope to find new inhibitors of the coronavirus polymerase that may later be developed into new antivirals. This is important to control local COVID-19 outbreaks that will occur even when large portions of the population are vaccinated. In the end, we have to also prepare for the next pandemic. If such drug development would have been carried out in the years after the SARS outbreak in 2002-03, we would be in a much better position now.
11 guiding principles for outstanding research
We asked Prof Cramer about his guiding criteria for conducting outstanding research and his advice for early-career researchers. Here is what he wrote:
- Choose an important open question to work on.
- Make sure you know what is known and what is unknown in your field and what are the key unresolved issues.
- Create an international network so you know what is going on.
- Try to find exceptionally motivated co-workers. And stay away from negative people.
- Implement a good lab culture and try to lead by example.
- Get enough money for your research – ideally enough to be limited by the best ideas, not money.
- It’s easy to get distracted and spend your time on things that are “interesting” and “doable.” But force yourself to concentrate on the big open questions, even if others tell you that chances for success are low. I heard it many times in my career that something is not doable. Now, looking back, things get done by students and postdocs that I could not even dream of when I started. The issue is that you have to get started and move in the right direction. Over time, the problem will appear in a different light – because some new paper comes out, a new technique is available or because you find something in the lab that leads to an unexpected solution.
- Make use of serendipity. This is not just chance. Instead, those who expect the unexpected will find it. Sometimes I do not see our chances, but then I have a great co-worker who does and I learn from them.
- When you have found something that is conceptually new and for certain — i.e., you have all needed controls — then publish immediately. The global community will make use of your information and the field advances more rapidly, and this will be beneficial for everyone.
- Go out and let others know what you find exciting — and seek input from others. Always remain open to learning new things. Seek advice at all stages of your career, in particular also from young scientists.
- Never give up.
The Otto Warburg Medal
As one of the most highly esteemed science awards in Germany, the Otto Warburg Medal has been conferred by the German Society for Biochemistry and Molecular Biology (GBM) since 1963. It honors outstanding, internationally recognized results in fundamental biochemical and molecular biological research.
Since 2012, GBM has been cooperating with Elsevier and its flagship title BBA – Biochemica et Biophysica Acta (BBA). From their early beginnings, both the GBM and Elsevier have been devoted to supporting and enhancing excellence in research. With the Otto Warburg Medal, they join forces to acknowledge pioneering achievements by outstanding international scientists, thereby inspiring young researchers and attracting the wider public’s interest in science. Elsevier and its journal BBA are the exclusive sponsors of this medal, with a prize of 25,000 Euros to support continued research by the awardees
Prof Patrick Cramer
Prof Patrick Cramer is Director of the Max Planck Institute for Biophysical Chemistry in Göttingen and Laureate for the 2020 Otto Warburg Medal. In 2019 he was awarded with the Ernst Schering Preis and 2006 with the prestigious Gottfried-Wilhelm-Leibniz-Preis.
Over the past 20 years, Prof Cramer has captured the atomic structure of RNA polymerase and many of its partner molecules. He thereby contributed to the development of special analytical methods. In addition to elucidating many detailed structures, he has shown how our genetic information is regulated and used in cells. Through his research, the basic principles of the transcription process and its regulation could be understood and made visible. In this way, diseases such as cancer, where the transcription of genetic material is misdirected, can be better researched.
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